Cocaine addiction remains a major public health issue, in part due to high rates of relapse. The disease is thought to arise from cellular adaptations involving dopamine (DA) transmission in mesocorticolimbic reward circuitry (the ventral tegmental area (VTA), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc) core). In laboratory animals, DA increases neuronal firing in the mPFC, and DA antagonists microinjected into the mPFC block relapse-like cocaine seeking (reinstatement). As a therapeutic target, however, reducing the actions of DA has limited potential due to multiple receptor subtypes, complex signal transduction, and numerous unwanted side effects. An alternative treatment strategy would be to target the effector mechanisms downstream of the intracellular signaling pathways stimulated by DA receptor activation that permit reinstatement of cocaine seeking. This proposal will focus on a DA-D1 receptor mediated closure of KCNQ type K+ channels in the PFC that reduces a form of intrinsic inhibition referred to as spike accommodation. Experiments in this proposal will test the hypothesis that following cocaine self-administration (SA), superactivation of DA-D1 receptor signaling (e.g., enduring accumulation of intracellular cAMP) results in a Ca2+ mediated closure of inhibitory KCNQ ion channels that eliminates spike accommodation in NAc core projecting mPFC pyramidal neurons. The resulting disinhibition removes an intrinsic brake on neuronal excitability. This hypothesis will be tested in two specific Aims with whole cell patch clamp electrophysiology. Using optogenetics and retrograde fluorescent microspheres, Aim 1 will test whether optogenetic (ChR2) stimulation of DA release from VTA terminals inhibits spike accommodation in both NAc core- and shell- projecting pyramidal cells in PFC slices from TH-Cre rats. Aim 2 will employ a behavioral rat model of cocaine SA and bath application of dopamine to stimulate DA D1-receptors to determine the extent to which cocaine SA treatment results in an enduring enhancement of Ca2+ release from intracellular stores, thereby diminishing KCNQ channel currents in core-projecting pyramidal cells. Preliminary data suggests that restoring this intrinsic inhibition by stabilizing KCNQ channels in the mPFC prevents cue-induced reinstatement of cocaine seeking. Therefore enhancing the function of KCNQ channels may represent a target for relapse prevention. In addition to providing insight into the cellular mechanisms by which DA regulates PFC activity after cocaine, this proposal provides the applicant with strong mechanistic training in cellular neuroscience using innovative optical tools and a translationally relevant animal model of addiction.